Natural products are unique sources of new lead compounds for the understanding and ultimate treatment of neurological disease. This proposal focuses on the synthesis and biological characterization of promising new small molecules based on the privileged yohimbine alkaloid scaffold. While these complex natural product alkaloids have been academic targets for synthesis over multiple decades, there is still a surprising lack of efficient, <10 step routes to provide new analogs of these classes of compounds containing high degrees of stereochemical information. Consequently, this dearth has limited the exploration of many yohimbine classes in discovery-based screening of CNS targets and represents a major gap in the knowledge. This high risk, high reward project will support both target and focused library synthesis of new privileged molecules and initial screening/validation of CNS activity in collaboration with a GPCR expert. This proposal brings together the complementary natural products chemistry and neuropharmacological expertise of the Scheidt and McCorvy laboratories. The objectives will be to: (1) synthesize mitragynine to establish the shortest route yet to this compound, and (2) create new mitragynine and yohimbine-like compounds and explore their potential as agonists and/or antagonists in CNS biology. This project will yield novel chemical tools for the pharmacological manipulation of CNS receptors and may lead to new therapeutic strategies for pain management and neurological diseases.

Public Health Relevance

New molecules that hold promise for treatment of common neuropsychiatric diseases and chronic nociceptive pain are discovered and developed from a variety of sources, including synthetic chemical libraries and natural organisms. This project capitalizes on our highly efficient yohimbine alkaloid synthesis platform to access and evaluate the novel mu-opioid receptor agonist mitragynine and completely new, focused libraries of previously inaccessible mitragynine/yohimbine analogs. Because these compounds potentially target multiple CNS receptors, they could be unique tools for understanding and ultimately treating neurological diseases and/or chronic nociceptive pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS120521-01
Application #
10143006
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Cywin, Charles L
Project Start
2020-09-01
Project End
2022-08-31
Budget Start
2020-09-01
Budget End
2022-08-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Chicago
State
IL
Country
United States
Zip Code
60611